"Effects of Long-Term Activation of the Adrenal Cortex and Antidepressant Treatments on the Splicing Pattern of the Large Conductance Potassium Channel mRNA in the Central Nervous System"

In order to facilitate adaptation, the stress-activated hypothalamo-pituitary-adrenal (HPA) axis adjusts the responsiveness of neuronal circuits responsible for regulating emotion, mood, behavior and neuroendocrine functions. However, prolonged activation of the adrenal cortex by persisting stressful conditions contributes to the development of mood disorders. The mechanism by which sustained overdrive of the HPA axis causes and/or exaggerates mood disorders is unclear.

It has been found recently that stress-hormones can influence alternative splicing of the calcium-dependent large-conductance potassium channels (BK _Ca channels) in adrenal chromaffin cells and in pituitary corticotrophs. Under elevated adrenocortical hormone secretion, the favored BK_Ca channel splice variant possesses increased Ca²⁺ and voltage sensitivities, as well as different susceptibility for various regulatory protein kinases. We hypothesize that a similar molecular mechanism is responsible for the changed responsiveness of mood-related neuronal circuits brought about by sustained adrenocortical activation. In order to test this hypothesis, we will use adult male rats to determine the influence of long-term elevation of adrenal steroids on the expression of BK_Ca channel splice variants. Tissue samples will be obtained by Palkovits’ microdissection method from brain areas relevant to mood disorders (prefrontal cortex, hippocampus, amygdala, and hypothalamus). Total RNA will be extracted and relative abundance of BK_Ca mRNA splice variants will be assessed with specific real-time PCR assays. In parallel experiments, we will investigate the influence of chronic antidepressant treatments on alternative splicing of BK_Ca channels. Subsequently, we will explore whether applications of antidepressants can bring about a reversal of the adrenal steroid induced alteration of BK_Ca channel pre-mRNA splicing.

These investigations may open up heretofore-unrecognized possibilities to interfere with the expression of a key intracellular signaling component (the BK_Ca channel) at the spliceosome level, thus offering novel ways to exploit this molecular interface for therapeutic purposes.